5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine has the following structure:

It is a triazolopyrimidine microtubule-active compound which has broad antitumor activity in in-vivo xenograft models of human non-small cell lung cancer (NSCLC), colon cancer, breast cancer, melanoma, and glioblastoma, including models which are resistant to taxanes or other microtubule-active compounds.
This class of triazolopyrimidine compounds is disclosed by Zhang et al. in US 2005/0090508, the disclosure of which is incorporated herein by reference in its entirety. A pharmaceutical formulation of a triazolopyrimidine compound is described in commonly assigned, co-pending patent Application Ser. No. 60/751,131, filed on Dec. 16, 2005, the disclosure of which is incorporated herein by reference in its entirety. The triazolopyrimidine compounds bind at the vinca site of β-tubulin, yet they have many properties that are similar to taxanes and distinct from vinca-site agents. In particular, these compounds enhance the polymerization of microtubule-associated protein (MAP)-rich tubulin in the presence of GTP at low compound:tubulin molar ratios, in a manner similar to paclitaxel and docetaxel. The triazolopyrimidine compounds also induce polymerization of highly purified tubulin in the absence of GTP under suitable experimental conditions, an activity that is a hallmark of taxanes. These compounds are potently cytotoxic for many human cancer cell lines in culture, including lines that overexpress the membrane transporters MDR (P-glycoprotein), MRP, and MXR, thus making them active against cell lines that are resistant to paclitaxel and vincristine. In particular, representative examples of this class of triazolopyrimidine compounds have high water solubility and can be formulated in aqueous solution. Representative examples of the triazolopyrimidine compounds are active as anti-tumor agents in athymic mice bearing human tumor xenografts of lung and colon carcinoma, melanoma, and glioblastoma, when dosed either intravenously or orally.
The physical and chemical properties of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine that results in challenges to the successful formulations of oral and liquid dosage forms include poor solubility in water and chemical instability due to several mechanisms. Specifically, 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine is not stable at room temperature and it undergoes dimerization as shown in Scheme 1 (the resulting product is hereinafter referred to as “Dimer”).
The dimers and related adducts are described in Application Ser. No. 60/751,166, as filed on Dec. 16, 2005, the disclosure of which is hereby incorporated by reference in its entirety. In particular, the dimers, adducts, methods for making and using same are incorporated by reference herein.

In addition, the hydrochloric acid salt of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl)}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine has been found to have good aqueous solubility, but the material is amorphous. Thus, there remains a need to identify a crystalline form of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine that is water soluble and has good stability under various storage conditions.
In accordance with the present invention, the 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine salts, including the succinate salts (anhydrous and dihydrate), the fumarate salts (dihydrate), and the mandelate salt, are provided in crystalline forms, described further hereinbelow.